rs369106578
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 6P and 4B. PM1PP3_StrongBS2
The NM_005343.4(HRAS):c.367C>T(p.Arg123Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,613,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R123P) has been classified as Uncertain significance.
Frequency
Consequence
NM_005343.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.367C>T | p.Arg123Cys | missense_variant | 4/6 | ENST00000311189.8 | |
HRAS | NM_176795.5 | c.367C>T | p.Arg123Cys | missense_variant | 4/6 | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.367C>T | p.Arg123Cys | missense_variant | 4/6 | 1 | NM_005343.4 | P1 | |
HRAS | ENST00000417302.7 | c.367C>T | p.Arg123Cys | missense_variant | 4/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251340Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135908
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461536Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727086
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 03, 2019 | Missense variants in this gene are often considered pathogenic (HGMD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 04, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jul 15, 2018 | - - |
Costello syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 29, 2023 | The HRAS c.367C>T (p.Arg123Cys) missense change has a maximum subpopulation frequency of 0.0086% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with Costello syndrome. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 123 of the HRAS protein (p.Arg123Cys). This variant is present in population databases (rs369106578, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with HRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 180851). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt HRAS function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 20, 2017 | The p.Arg123Cys variant in HRAS has not been previously reported in individuals with clinical features of Noonan syndrome disorders, but has been reported in Cl inVar by other clinical laboratories (VariationID: 180851). This variant has bee n identified in 3/33582 Latino chromosomes and 3/111670 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSN P rs369106578). Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predic tive enough to determine pathogenicity. In summary, the clinical significance o f the p.Arg123Cys variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at